CA2150036C

CA2150036C - A material for a bone substitute and the manufacturing method thereof

Info

Publication number: CA2150036C
Application number: CA002150036A
Authority: CA
Inventors: Tadashi Kokubo
Original assignee: FOUNDATION FOR PROMOTION OF ION ENGINEERING (THE)
Current assignee: Sagawa Printing Co Ltd
Priority date: 1993-11-09
Filing date: 1994-11-07
Publication date: 2001-07-10
Anticipated expiration: 2014-11-07
Also published as: NO310060B1; FI115445B; CN1115170A; NO951567L; KR950704004A; EP0678300A4; AU8115794A; FI952234A; DE69424035D1; CA2150036A1; EP0678300A1; KR0149134B1; CN1101705C; ATE191856T1; DK0678300T3; NO951567D0; AU671567B2; ES2147831T3; DE69424035T2; WO1995013100A1

Abstract

It is an object of the present invention to offer a material suitable for use as a bone substitute, which provides both the fracture toughness of titanium and the bioactivity of apatite, wherein titanium and apatite is tightly adhered, and which is available at low cost. The material is produced by soaking a substrate made of titanium Ti or titanium Ti alloys into alkaline solution, followed by heating of the said substrate to the level of at most the titanium Ti transition temperature.

Description

~~ ~oo~s DESCRIPTION
A Material for a Bone Substitute and the Manufacturing Method Thereof Technical Field This invention relates to a material suitable for use as a bone substitute and the manufacturing method thereof. This material for a bone substitute may be utilized effectively as a preparing material for parts where a large load is applied, such as femoral bones, hip joints and tooth roots.
Background Art The criterion considered for an artificial material to exhibit bioactivity, i . e. , an ability to bond with bones in the body, is the material' s capability of forming an apatite layer, which is of the same type as the inorganic components in bone, on their surface .
Conventionally employed materials for a bone substitutes which exhibit such a characteristic are: Na20-Ca0-SiOz-Pz05 glass, sintered hydroxyapatite ( Calo ( P04 ) 6 ( OH ) 2 ) , and Mg0-Ca0-SiOz-P205 glass-ceramic. These are superior materials with a bioactivity, a characteristic to form an apatite layer similar to the inorganic components in bone on their surface in the body, and to bond with bones directly. However, their values of fracture toughness ( 1 to 2 MPaml~~ ) are not nearly comparative to that of a human cortical bone ( 2 to 6 MPaml~Z ) , therefore they may not be utilized as a material for substituting in the hip joints and tibial bones where a large load is applied.
Therefore, the substitute materials currently utilized in ~1a41136 these locations are titanium, which exhibits the most superior biocompatibility among the metallic materials, and its alloys.
These metallic materials possess a large value of fracture toughness, however they take a long time, about ten years, to directly bond with bones .
Therefore, a bioactivity has been provided to these metallic materials, by the method of plasma coating, to cover their surface with a molten hydroxyapatite. The materials obtained by this method offer both the fracture toughness of titanium and the bioactivity of apatite.
However, there are the following problems in the' preparation method by the plasma coating: (1) necessity of an expensive plasma spray instrument, (2) difficulty in controlling the composition and the crystallinity of the hydroxyapatite formed on the metallic substrate surface since the hydroxyapatite powder, the sprayed material, is instantaneously but once exposed to about 30, 000 ~C of high temperature, ( 3 ) difficulty in forming a dense apatite layer since the method only sediments the half-molten hydroxyapatite powder on the substrate by free fall, and ( 4 ) difficulty in forming a strong bond of the apatite layer to the substrate due to the same reason as above .
Disclosure of Invention It is an object of the present invention to solve these conventional problems and to offer the material for a bone substitute, which provides both the fracture toughness of titanium and the bioactivity of apatite, wherein titanium and apatite are tightly adhered, and which is available at low cost.
To achieve the above object, the material for a bone substitute of the present invention comprises a substrate made of titanium (Ti) or titanium (Ti) alloys and a surface layer (a primary surface layer) formed on the surface of the substrate, said primary surface layer comprising a titanium oxide phase and amorphous phases of alkali titanates. As a substrate, pure Ti is desirable from the view point of biocompatibility, while alloys thereof such as Ti-6A1-4V, Ti-5A1-2.5Sn, Ti-3A1-13V-llCr, Ti-l5Mo-5Nb-3Ta, Ti-6A1-2Mo-Ta are preferred from the forming view point.
In addition, the material is optionally provided with a second layer, of which the main constituent is apatite, further on top of the primary surface layer.
The desirable type of the primary surface layer has a gradually decreasing concentration of the titanium oxide phase towards the outer surface, along with a gradually increasing concentration of the total alkali ions towards the outer surface.
The desirable thickness of the primary surface layer is about 0. 1 to 10 um, preferably about 1 ~Cm, while that of the second layer is at least 1 ~Cm, preferably about 10 ,gym.
The suitable production method to prepare the said materials for a bone substitute comprises soaking the substrate made of titanium (Ti) or titanium (Ti) alloys into alkaline solution, followed by heating the resultant substrate to the level of at most the titanium ( Ti ) or titanium alloys transition temperature.
To make both the soaking step and the heating step progress at the same time, the soaking step may be conducted at a very high temperature under pressure. In addition, after the heat treatment, the substrate may be soaked into the aqueous solution which contains calcium ( Ca ) and phosphorous ( P ) to a level of , at least, the apatite solubility, such as the simulated body fluid.
Here, the alkaline solution is desirably an aqueous solution which contains at least one of the following ions: sodium ions Na+, potassium ions K', and calcium ions CaZ'. The heating temperature is desirable from 300 to 800 °C, and more preferably from 550 to 650 °C, Originally there exists an extremely thin film on the surface 21~0~3~

of titanium ( Ti ) or titanium ( Ti ) alloys, which comprises oxides similar TiOz. Ti02 is an amphoteric substance which reacts with both strong acids and bases. Therefore, soaking of the substrate made of titanium ( Ti ) or titanium alloys into alkaline solution results in the amorphous alkali titanates on the substrate surface with a concentration gradient gradually increasing from the inside where very little reaction takes place, to the outside where more reaction occurs . Then the substrate is heated to the level of at most the titanium ( Ti ) or titanium alloys transition temperature, which causes the diffusion of oxygen and increases the thickness of the said formed phase.
By this method, the surface layer consisting essentially of the titanium oxide phase and the amorphous alkali titanate phase is formed on the surface of the substrate. In addition, the alkali titanate produced by the intermediate process exhibits a gradual concentration gradient, wherein the alkali titanate concentration gradually increases toward the outside along the surface thickness direction. Therefore the titanium oxide phase, the starting material of the said compound, gradually decreases toward the outside. On the other hand, the total concentration of alkali ions ( Na', K', and Ca2' and so on ) consisted in the product component, an amorphous alkali titanate phase, increases gradually toward the outside. The slopes of these concentration changes are so gradual that the interface between the substrate and the surface layer and the boundaries among the phases within the surface layer are tightly bonded. This is the major difference from the case when substrate is soaked into a preliminarily prepared titanic gel in order to form a gel which easily bonds to bones on the Ti surface, but because the adhesive strength between the Ti and the gel layer is weak, the layer can be peeled off. In the present invention the outer surface is rich in alkali ions, which can be exchanged with hydrogen ions within a simulated body fluid or a actual body fluid, to form a titanium hydroxide phase which readily reacts with calcium (Ca) and phosphorous (P).
On the other hand, the aqueous solutions or body fluids which consist of calcium ( Ca ) and phosphorous ( P ) at a level at least of the apatite's solubility comprise the components which grow apatite. Therefore they are capable of growing apatite crystals.
However, in reality, the activation energy for the nucleation of the apatite is so high that this barrier prevents spontaneous nucleation of the apatite in the solution or body fluid. On the other hand, the amorphous titanium hydroxide phase formed by the hydration of alkali titanate phase is highly reactive owing to its amorphous structure. Therefore it forms apatite nuclei by reacting with the bone forming components in the body fluid.
Further, apatite nuclei may be preliminarily formed by being soaked into the aqueous solution, more desirably the simulated body fluids, which consist of calcium ( Ca ) and phosphorous ( P ) at a level of at least the apatite's solubility, after the heat treatment. Those particularly treated by the simulated body fluid which possesses the ion concentration close to that of the actual body fluid easily bond with bones, since the composition and the structure of the apatite formed on the surface is very similar to those of bones.
Here, the heat treatment temperature less than 300 ~C will not permit diffusion of air into the material at a satisfactory rate, thereby leading to an insufficiency of oxygen supply in the surface layer. As a result, the primary surface layer will not be thick enough and its ability to form apatite on its surface in the body will be inferior. On the other hand, the temperature over 800 ~C undesirably reaches to the transition temperature of Ti.
When the transition takes place in the titanium ( Ti ) or titanium (Ti) alloy substrate, its mechanical strength deteriorates.
Brief Description of Drawings ~la0~J3~

Figure 1 indicates the result of thin layer X-ray diffraction analysis performed on the test plates which were heat-treated at 600 °C after being soaked in the NaOH solution, then soaked into the simulated body fluid.
Best Mode for Carrying Out the Invention Titanium ( Ti ) metal plates of 15 X 10 X 1 mm3 size were polished with #400 diamond paste, washed with acetone and subsequently with distilled water. These plates were soaked in either 10 M-NaOH or -KOH aqueous solutions at 60 °C for 24 hours. Then these test plates were washed with distilled water using a sonic cleaner for at least 20 minutes . Their surfaces were observed to be of a uniform yellow tint and of a uniform yellow for the plates soaked in NaOH and KOH, respectively, which confirmed the formation of alkali titanates.
Then, the Ti metal plates were placed in a furnace and the temperature was raised to 400, 500, 600 and 800 °C at a heating rate of 5 °C/min, and maintained at these given temperatures for an hour. The changes in the surface structure of the titanium metal plates after the said treatments were observed by the methods of thin film X-ray diffraction and scanning electron microscope-energy dispersive X-ray analysis (SEM-EDX).
In the thin film X-ray diffraction photograph of the test plates after being soaked in alkali solutions, broad peaks caused by the amorphous phase were observed at a 2 B value between 23 and °C. The formation of this phase is attributed to the reaction between titanium oxide and alkali ions . As the temperature of the plate heat treatment increases, the intensity of the titanium 30 oxide crystalline phase peak also increased in the X-ray diffraction. When the heating temperature is at most 600 °C, there existed also the peaks of the amorphous phase. On the other hand, the heat treatment at 800 °C resulted in the disappearance 21~0~3~
of the amorphous phase peak and, instead many peaks of crystalline titanium oxide and alkali titanates appeared. On the surface of the test plate which was heat-treated at 600 ~C, there was about 1 ,um thickness of an amorphous layer, which covered the surface of the titanium metal uniformly. Further, the cross-section SEM-EDX observation of the test plate which was heat treated at 600 ~C after soaking in KOH solution revealed that the concentration of potassium is gradually decreasing from the surface to the inside of the amorphous layer.
These results are summarize in Table 1.

~~~OU35 Table 1 No.Alkali Heating Constitution Phase of Appearance Solution Temp.( C) the Primary Surface Layer .

1 NaOH 400 Ti+ Amorphous TiOz + Uniform Amorphous alkali titanate 2 NaOH 500 Ti + Rutile + Amorphous Uniform TiOz +

Amorphous alkali titanate 3 NaOH 600 Ti + Rutile + Uniform Amorphous alkali titanate 4 NaOH 800 Ti + Rutile + Na2Ti501z Uniform KOH 400 Ti + Amorphous Ti02 + Uniform Amorphous alkali titanate 6 KOH 500 Ti + Anatase + Amorphous Uniform Ti02 +

Amorphous alkali titanate 7 KOH 600 Ti + Anatase + Uniform Amorphous alkali titanate 8 KOH 800 Ti+ Anatase + KzTi501z Uniform + KZTi03 ~laa~~~

As seen in Table 1, the crystalline titanium oxide phases ( a rutile type and an anatase type ) and amorphous alkali titanate phases have been formed on the surface of the Ti metal plates which were heat-treated at the temperature from 400 to 600 °C. On the other hand, the amorphous alkali titanate phase has disappeared from the Ti metal surface heated at 800 °C, and the crystalline phase of NaZTi501Z was confirmed, instead.
Then, the obtained test plates were soaked into the simulated body fluid which consists of the inorganic ion concentration almost equal to human body fluid, and the formation of apatite layer was examined. The simulated body fluid was prepared by having the following ion concentrations: K', 5.0; Na', 142; Mgz', 1.5; Ca2', 2.5; Cl', 148; HC03', 4.2; HP042', 1.0; and 5042', 0.5;
each in mM units, and by having its pH value controlled to 7.4 at 37°C by tri-(hydroxy methyl)-aminomethane and hydrochloric acid.
Figure 1 indicates the result of thin film X-ray diffraction analysis performed on the test plates which were heat-treated at 600 °C after being soaked in the NaOH solution, then subsequently soaked into the simulated body fluid. Within the two weeks of soaking, apatite started to grow on the surface. After three weeks, the grown apatite layer covered the surface and the titanium metal peaks were hardly observed. After soaking for three weeks, the apatite layer with a 5 to 10 um thickness formed on the surface of the titanium metal homogeneously. The same tendency was also observed for test plates heat-treated at 400 °C
and 500 °C .
Industrial Applicability A material for a bone substitute and its manufacturing method in the present invention consist of the said constitution, therefore they offer the following remarkable effects.
The manufacturing process involves a simple heating after ~a_~oo~o 1~
soaking the Ti metal into the alkali solution, thereby avoiding any expensive device. When this material is inserted in the body, the apatite, which is the same as the inorganic components in bones, forms naturally on its surface. Through the apatite, the material bonds with bones tightly. Further, when the material is soaked into the aqueous solution which comprises calcium ions and phosphorous ions at the level which exceeds the saturated concentration of apatite, or more desirably into the simulated body fluid, the apatite, which is the same as the inorganic components in bones, forms on the material's surface. Through the apatite, the material bonds with bones tightly.
Consequently, this material is superior in biocompatibility.
In addition, the substrate made of Ti metal and the second surface layer made of apatite bond through the primary surface layer made of titanium oxide and so on, by the means of chemical bonding and with a gradual concentration slope. Therefore, the adhesive strength of apatite towards the substrate is large.

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:-

1. A material suitable as a bone substitute which comprises a substrate made of titanium Ti or titanium Ti alloys and a primary surface layer formed on the surface of the substrate, said primary surface comprising a titanium oxide phase and amorphous phases of alkali titanates.

2. The material according to claim 1, wherein the material possesses a second layer, mainly comprising apatite, further on top of the said primary surface layer.

3. The material according to claim 1, wherein the concentration of said titanium oxide phase in the primary surface layer is gradually decreasing towards the outer surface, while the concentration of total alkali ions in the primary surface layer is gradually increasing towards the outer surface.

4. The material according to claim 2, wherein the concentration of said titanium oxide phase in the primary surface layer is gradually decreasing towards the outer surface, while the concentration of total alkali ions in the primary surface layer is gradually increasing towards the outer surface.

5. The material according to any of claims 1 through 4, wherein the thickness of the primary surface layer is 0.1 to 10 µm.

6. The material according to any of claims 2, 4, or 5 as dependent on claim 2 or 4, wherein the thickness of the second layer is at least 1 µm.

7. A process for producing a material suitable as a bone substitute, comprising the steps of:
soaking a substrate made of titanium Ti or titanium Ti alloys into alkaline solution; and followed by heating the substrate to a heating temperature which is in the range from 550 to 650°C.

8. A process for producing a material suitable as a bone substitute, comprising the steps of:
soaking of a substrate made of titanium Ti or titanium Ti alloys into alkaline solution;
heating the substrate to a heating temperature which is in the range from 301 to 799°C; and soaking in an aqueous solution which contains calcium ions and phosphate ions to a level of, at least, apatite solubility.

9. A process according to claim 8 wherein the heating temperature is in the range from 550 to 650°C.

10. The process according to claim 8 or claim 9, wherein the said alkaline solution contains at least one of:
sodium ions Na+, potassium ions K+, and calcium ions Ca2+.

11. A bone repairing material comprising a substrate of titanium or a titanium alloy and on the surface of the substrate a primary surface layer comprising a titanium oxide phase and an amorphous phase of alkali titanate, said primary surface layer thereby forming an interface between said substrate and primary surface layer, said primary surface layer having an interior and an outer surface, said primary surface layer comprising a titanium oxide phase and an amorphous phase of alkali titanate, said primary surface layer having been treated so as to provide a layer comprising amorphous alkali titanate phase and a sufficient concentration gradient of alkali and titanium ions to permit apatite from natural or simulated body fluid to be grown thereon and wherein the concentration of titanium oxide phase in the primary surface layer gradually decreases from the layer interior towards the outer surface, while the concentration of the total alkali ions in the primary surface layer gradually increases from the layer interior towards the outer surface, and wherein said interface between said substrate and said primary surface layer and boundaries of the phases within the surface layer are tightly bonded, said primary surface layer having been heated in a gas comprising oxygen to from about 300°C. to not more than the titanium or titanium alloy transition temperature, for about 1 to 24 hours.

12. A material according to claim 11, further comprising a layer of apatite on top of the said primary surf ace layer.

13. A material according to claim 11, wherein the thickness of the primary surface layer is 0.1 to 10 µm.

14. A material according to claim 12, wherein the thickness of the primary surface layer is 0.1 to 10 µm.

15. A material according to claim 12, wherein the thickness of the apatite layer is at least 1 µm.

16. A method of producing a material useful as a bone substitute comprising heating a substrate of titanium or titanium alloy and on the surface of the substrate a primary surface layer comprising a titanium oxide phase and an amorphous phase of alkali titanate, said primary surface layer thereby forming an interface between said substrate and primary surface layer, said primary surface layer having an interior and an outer surface, said primary surface layer comprising a titanium oxide phase and an amorphous phase of alkali titanate, said primary surface layer having been treated so as to provide a layer comprising amorphous alkali titanate and a sufficient concentration gradient of alkali and titanium ions to permit apatite from natural or simulated body fluid to be grown thereon and wherein the concentration of titanium oxide phase in the primary surface layer gradually decreases from the layer interior towards the outer surface, while the concentration of the total alkali ions in the primary surface layer gradually increases from the layer interior towards the outer surface, and wherein said interface between said substrate and said primary surface layer and boundaries of the phases within the surface layer are tightly bonded, said heating being conducted in a gas comprising oxygen to a temperature from about 300°C. to not more than the titanium or titanium alloy transition temperature, for about 1 to 24 hours.

17. A method according to claim 16, further comprising soaking the resultant product in an aqueous solution comprising calcium and phosphorous in a concentration level of, at least, apatite solubility.

18. A method according to claim 16, wherein the amorphous alkali titanate phase was formed by soaking the titanium or titanium alloy in an alkaline solution containing at least one of: sodium ions NA+, potassium ions K+, and calcium ions Ca2+.

19. A method according to claim 16, wherein the heating temperature is from 300° to 800°C.

20. A method according to claim 16, wherein the heating temperature is from 550° to 650°C.

21. A method according to claim 19, wherein the heating is conducted for about 1-24 hours.

22. A method according to claim 20, wherein the heating is conducted for about 1-24 hours.

23. A material according to claim 11, wherein the heating temperature is from 300° to 800°C.

24. A material according to claim 11, wherein the heating temperature is from 550° to 650°C.